Abstract
Persistent acinar to ductal metaplasia (ADM) is a recently recognized precursor of pancreatic ductal adenocarcinoma (PDAC). Here we show that the ADM area of human pancreas tissue adjacent to PDAC expresses significantly higher levels of regenerating protein 3A (REG3A). Exogenous REG3A and its mouse homolog REG3B induce ADM in the 3D culture of primary human and murine acinar cells, respectively. Both Reg3b transgenic mice and REG3B-treated mice with caerulein-induced pancreatitis develop and sustain ADM. Two out of five Reg3b transgenic mice with caerulein-induced pancreatitis show progression from ADM to pancreatic intraepithelial neoplasia (PanIN). Both in vitro and in vivo ADM models demonstrate activation of the RAS-RAF-MEK-ERK signaling pathway. Exostosin-like glycosyltransferase 3 (EXTL3) functions as the receptor for REG3B and mediates the activation of downstream signaling proteins. Our data indicates that REG3A/REG3B promotes persistent ADM through binding to EXTL3 and activating the RAS-RAF-MEK-ERK signaling pathway. Targeting REG3A/REG3B, its receptor EXTL3, or other downstream molecules could interrupt the ADM process and prevent early PDAC carcinogenesis.
Highlights
Persistent acinar to ductal metaplasia (ADM) is a recently recognized precursor of pancreatic ductal adenocarcinoma (PDAC)
We demonstrated the involvement of regenerating protein 3A (REG3A)/ REG3B in the ADM process using several models including: human pancreas tissue from patients with PDAC, in vitro cultures of primary human and murine pancreatic acinar cells, an in vivo transgenic mouse model with caerulein-induced pancreatitis, and recombinant REG3B-treated wild-type mice with caerulein-induced pancreatitis
The level of Reg3a mRNA in ADM area was nearly 2-fold higher than in normal pancreatic tissue (Supplementary Fig. 2a). This data suggests that REG3A protein and mRNA are highly expressed in human ADM
Summary
Persistent acinar to ductal metaplasia (ADM) is a recently recognized precursor of pancreatic ductal adenocarcinoma (PDAC). Exogenous REG3A and its mouse homolog REG3B induce ADM in the 3D culture of primary human and murine acinar cells, respectively Both Reg3b transgenic mice and REG3B-treated mice with caerulein-induced pancreatitis develop and sustain ADM. Two out of five Reg3b transgenic mice with caerulein-induced pancreatitis show progression from ADM to pancreatic intraepithelial neoplasia (PanIN) Both in vitro and in vivo ADM models demonstrate activation of the RAS-RAF-MEK-ERK signaling pathway. We demonstrated the involvement of REG3A/ REG3B in the ADM process using several models including: human pancreas tissue from patients with PDAC, in vitro cultures of primary human and murine pancreatic acinar cells, an in vivo transgenic mouse model with caerulein-induced pancreatitis, and recombinant REG3B-treated wild-type mice with caerulein-induced pancreatitis. We identified a candidate receptor for REG3B on the acinar cell membrane, and unveiled the downstream signaling pathway that leads to ADM formation and maintenance
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